Early Switch to Fulvestrant Plus Palbociclib Improves Outcomes in ESR1-Mutated, Estrogen Receptor-Positive Metastatic Breast Cancer

For patients with estrogen receptor-positive metastatic breast cancer who are treated with palbociclib plus an aromatase inhibitor, the strategy of switching to palbociclib plus fulvestrant upon detection of a resistance mutation more than doubled progression-free survival, according to results from the phase III PADA-1 trial.

Estrogen receptor gene (ESR1) mutations restore the ligandindependent activity of the estrogen receptor (ER) in patients with ER-positive metastatic breast cancer. Although these mutations are associated with resistance to aromatase inhibitor (AI) therapy, tumors harboring mutated ESR1 retain their sensitivity to selective estrogen receptor degraders (SERDs). Mutations in ESR1 are rare at diagnosis, occurring in <5% of patients with metastatic breast cancer. However, the prevalence of ESR1 mutations increases to 30% to 40% among patients whose disease progresses on first-line aromatase inhibitor therapy.
The presence of ESR1 mutations in the blood (bESR1), detected by cell-free circulating DNA analysis, is associated with resistance to aromatase inhibitor therapy, but not to treatment with fulvestrant or palbociclib.
The phase III PADA-1 trial was designed to evaluate the feasibility of preventing or delaying tumor progression in patients receiving first-line treatment with palbociclib plus aromatase inhibitor therapy by switching from an AI to fulvestrant as soon as a bESR1 mutation becomes detectable, while also maintaining treatment with palbociclib.

Study Design
The PADA-1 trial enrolled 1,017 patients with ER-positive/ HER2-negative metastatic breast cancer who were undergoing first-line treatment with palbociclib plus an aromatase inhibitor. Patients provided blood samples for bESR1 mutation screening at enrollment, at month 1, and every 2 months thereafter. Blood samples were monitored for several ESR1 mutations: E380, P535, L536, Y537, and D538.
Monitoring revealed a new ESR1 mutation in 172 patients who did not experience concurrent disease progression. The median time from trial enrollment to detection of the ESR1 mutation was 14.2 months (range, 2.8 to 47.1 months). Patients with a newly detected mutation were randomly assigned to 1 of 2 treatment approaches: • Maintain treatment with palbociclib plus an aromatase inhibitor (n = 84) • Switch treatment to palbociclib plus fulvestrant (n = 88) The co-primary endpoints were progression-free survival (PFS) and grade ≥3 hematologic adverse events.
Baseline characteristics were similar in both treatment groups ( Table 1). The median patient age was approximately 61 years, and one-third of patients (34%-37%) had prior treatment with an aromatase inhibitor.

Key Findings
After a median follow-up of 26 months, the strategy of switching patients from an aromatase inhibitor to fulvestrant upon bESR1-mutation detection was associated with a 39% reduction in the risk of disease progression or death ( Table 2). The median PFS for patients who were switched to fulvestrant was 11.9 months, compared with 5.7 months for patients who remained on an aromatase inhibitor (HR, 0.61; p =.005).
Among those who were randomized to the aromatase inhibitor arm, 69 patients progressed and were given the option to crossover to the fulvestrant arm. Of those who switched to fulvestrant (n = 47), the second median PFS was 3.5 months. This suggests that second-line fulvestrant confers a benefit for a brief duration and underscores the importance of detecting ESR1 mutations early.
The analysis of the co-primary endpoint of grade ≥3 hematologic adverse events found no safety signals associated with switching from an aromatase inhibitor to fulvestrant (Table 3). Dose reductions were similar in the palbociclib plus aromatase inhibitor (7.1%) and palbociclib plus fulvestrant (7.9%) groups. One patient in the fulvestrant group (1.1%) withdrew from the trial due to a treatment-related adverse event.
Findings from the PADA-1 trial support a personalized approach to treatment modification based on the early detection of ESR1 mutations in patients with ER-positive metastatic breast cancer. Results also demonstrate the utility of targeting the brief window of opportunity-after the initiation of first-line therapy but before tumor progression-to improve patient outcomes in patients who develop resistance mutations.